Rho Kinase Inhibitors

Rho kinase (ROCK) is a serine/threonine kinase that serves as an important downstream effector of Rho guanosine triphosphate hydrolase (Rho GTPase). The Rho family of GTPases is composed of small (≈21 kDa) signaling G proteins (also known as guanine nucleotidebinding proteins) found in the cytosol and has 3 main classes: Rho, Rac, and Cdc42.

The Rho class has 3 isoforms: RhoA, RhoB, and RhoC. RhoA is activated by guanine nucleotide exchange factors. Upon binding to GTP, RhoA activates ROCK, which phosphorylates several downstream substrates involved in a wide variety of cellular functions. Two isoforms, ROCK-I and ROCK-II, have been isolated.

ROCK plays a critical role in regulating the tone of smooth muscle tissues. Animal studies have demonstrated increased ocular blood flow presumably through the relaxation of vascular endothelial smooth muscle, as well as the neuroprotective promotion of retinal ganglion cell survival and axon regeneration. ROCK inhibitors may also reduce scarring after glaucoma filtering surgery by blocking the assembly and contraction of transforming growth factor β-induced stress fibers and inhibiting fibroproliferation and collagen deposition postoperatively.

ROCK inhibitors have also been proposed for the treatment of corneal endothelial decompensation. Topical ROCK inhibitors have promoted cell proliferation in animal models, and pilot clinical research suggests a similar response in humans. ROCK inhibitors are being studied for wound healing in the corneal endothelium, Fuchs endothelial corneal dystrophy, and corneal decompensation after cataract surgery, as well as for enhancing engraftment of corneal endothelial cells onto recipient tissues in tissue engineering therapy.

Selective ROCK inhibitors are thought to increase aqueous humor drainage through the TM, subsequently decreasing IOP. The exact molecular mechanism has not been fully elucidated. ROCK inhibitors appear to have several actin cytoskeletal-related targets that directly affect the contractile properties of TM outflow tissue.

In 2014, the ROCK inhibitor ripasudil, 0.4%, twice-daily ophthalmic solution was approved in Japan for the treatment of glaucoma and ocular hypertension when other therapeutic drugs are not effective or cannot be administered. Another agent, netarsudil, is an inhibitor of both ROCK and the norepinephrine transporter. Netarsudil is thought to work via 3 mechanisms:

• increase of trabecular outflow

• reduction of episcleral venous pressure by ROCK inhibition

• reduction of aqueous production by norepinephrine transporter inhibition

In a phase 3 clinical trial, netarsudil was associated with a 3.3- to 4.6-mm Hg reduction in IOP. In another study, netarsudil, 0.02%, dosed once daily was noninferior to timolol, 0.5%, dosed twice daily. The drug is currently FDA approved for the reduction of IOP. Common adverse effects include hyperemia (up to 53% of study eyes), cornea verticillata (20% of study eyes), irritation, and blurred vision.

Fixed-combination therapy with netarsudil, 0.02%, and latanoprost, 0.005%, is also available.

• Okumura N, Okazaki Y, Inoue R, et al. Effect of the rho-associated kinase inhibitor eye drop (ripasudil) on corneal endothelial wound healing. Invest Ophthalmol Vis Sci. 2016; 57(3):1284–1292.

• Serle JB, Katz LJ, McLaurin E, et al; ROCKET-1 and ROCKET-2 Study Groups. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116–127.

• Tanna AP, Johnson M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology. 2018;125(11):1741–1756.

Table 16-12 Fixed-Combination Glaucoma Medications

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.